Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Graduate School of Health Sciences, Kumamoto Health Science University, Kumamoto 861-5598, Japan; Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
J Neurol Sci. 2017 Sep 15;380:205-211. doi: 10.1016/j.jns.2017.07.030. Epub 2017 Jul 27.
Naftopidil is used clinically for the treatment of voiding disorders in benign prostatic hyperplasia. Previous in vivo experiments in which naftopidil was applied intrathecally abolished rhythmic bladder contraction, suggesting that naftopidil might inhibit a voiding reflex through interaction with spinal dorsal horn neurons. Here we aimed to clarify the mechanism of action of naftopidil on dorsal horn neurons.
Whole-cell patch-clamp recordings were performed using substantia gelatinosa neurons of adult rat spinal cord slices. Miniature or evoked inhibitor and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were analyzed.
Bath-applied naftopidil increased the frequency but not the amplitude of miniature IPSCs (mIPSCs) in 38% of neurons tested; in contrast, the effect of naftopidil on miniature EPSCs (mEPSCs) were mild and observed in only 2 out of 19 neurons. Naftopidil enhanced the amplitude of both GABAergic and glycinergic evoked-IPSCs (eIPSCs) that were elicited by focal stimuli in the presence of either the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV).
Although naftopidil was developed as an alpha-1 adrenoceptor antagonist, our previous spinal cord slice experiments showed that the activation of an alpha-1 adrenoceptor in substantia gelatinosa increases the frequency of mIPSCs. This result suggested that, under our conditions, naftopidil may interact with a receptor(s) other than an alpha-1 adrenoceptor in the spinal dorsal horn. The present results suggested that naftopidil enhances the release of GABA and glycine by activating inhibitory interneuron terminals in the spinal dorsal horn via a receptor other than an alpha-1 adrenoceptor, thereby modulating sensory transmission in the substantia gelatinosa.
那夫替丁临床上用于治疗良性前列腺增生的排尿障碍。先前的体内实验表明，鞘内给予那夫替丁可消除节律性膀胱收缩，提示那夫替丁可能通过与脊髓背角神经元相互作用抑制排尿反射。本研究旨在阐明那夫替丁对背角神经元的作用机制。
使用成年大鼠脊髓切片的胶状质神经元进行全细胞膜片钳记录。分析微小或诱发的抑制性和兴奋性突触后电流（分别为 IPSCs 和 EPSCs）。
在 38%测试的神经元中，浴液给予那夫替丁增加了微小 IPSC（mIPSCs）的频率但不增加其幅度；相比之下，那夫替丁对微小 EPSC（mEPSCs）的作用较弱，仅在 19 个神经元中的 2 个中观察到。那夫替丁增强了 GABA 能和甘氨酸能诱发 IPSC（eIPSCs）的幅度，这些 IPSC 是在存在非 NMDA 受体拮抗剂 6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）或 NMDA 受体拮抗剂 DL-2-氨基-5-磷基戊酸（APV）的情况下，由局灶性刺激引起的。
尽管那夫替丁被开发为α1肾上腺素受体拮抗剂，但我们之前的脊髓切片实验表明，胶状质中α1肾上腺素受体的激活增加了 mIPSCs 的频率。这一结果表明，在我们的条件下，那夫替丁可能与脊髓背角中的一种不同于α1肾上腺素受体的受体相互作用。本研究结果表明，那夫替丁通过激活脊髓背角中的抑制性中间神经元末梢，增强 GABA 和甘氨酸的释放，从而调节胶状质中的感觉传递。
